Albuminuria is the single strongest predictor of kidney function decline and is associated with the presence and severity of cardiovascular disease and predicts mortality. Dysfunction of podocytes is the major culprit of glomerular disease causing albuminuria. The demonstrated role of podocyte TRPC5 signaling in the onset of albuminuria suggests therapeutic benefit in progressive glomerular diseases such as Focal Segmental Glomerulosclerosis (FSGS), a histopathological diagnosis with different pathogeneses including genetic mutations, drugs, viral infections, and most importantly, as the result of metabolic disease, such as diabetes, obesity and hypertension. As it stands, FSGS remains a devastating and largely untreatable disease associated with increased morbidity. We have previously demonstrated that a novel TRPC4/5 antagonist, ML204, is able to protect the kidney filter. However, highly potent and selective antagonists of TRPC5 have not been identified yet. In this proposal, we will improve and optimize our initial lead compound, ML204, and test its ability to reduce proteinuria in rodent models of disease. In order to develop these first-in-class compounds, we will utilize an iterative medicinal chemistry approach and integrated DMPK studies which will allow us to evaluate not only potency and selectivity; but also the in vitro and in vivo DMPK properties of newly made compounds in a timely manner. These selective TRPC5 antagonists not only offer a unique opportunity to test the hypothesis in this proposal, but also, to help advance the field towards a drug development.